The present invention relates generally to synthetic methods for the preparation of lactams. More particularly, the present invention relates to efficient and economic synthetic methods for the preparation of optionally substituted lactams by intramolecular Cxe2x80x94H insertion reactions of xcex1-diazoamides, in which the xcex1-diazoamides are activated for intramolecular Cxe2x80x94H insertion, for example by sulfone substitution, and to compounds and libraries of compounds derived therefrom.
Lactacystin, an exemplary chiral pyrrolidinone, possesses structural motifs common to a number of biologically active natural products such as kainic acid and epolactaene. These molecules, or their synthetic precursors, contain lactam cores (specifically, xcex3-lactam cores) that are highly functionalized. Numerous medicinal applications of such xcex3-lactam systems are known, encompassing applications as diverse as, for example, anticancer agents, psychotropic agents, neuromuscular transmission blockers, immunoregulators, neurological excitants, protease inhibitors, and antidepressants. Therefore, a general, efficient and economic synthesis of such chiral pyrrolidinones would facilitate ongoing and future health related research.
The pyrrolidinone functionality is a prevalent theme in various syntheses, and serves as a crucial intermediate in the synthesis of numerous natural products. Although a large number of synthetic methods have been reported to date (see, for example, DiCosimo, R., Gavagan, J. E., Fager, S. K., Fallon, R. D., Folsom, P. W., Herkes, F. E., Eisenberg, A., and Hann, E. C. xe2x80x9cChemoenzymatic Production of Lactams from Aliphatic xcex1,xcfx89-Dinitrilesxe2x80x9d 1998, J. Org. Chem. 63:4792), the reported asymmetric syntheses are inefficient, lengthy, and costly (see, for example, Meyers, A. I. and Burgess, L. E. xe2x80x9cAsymmetric Synthesis of xcex3,xcex3-Dialkyl-xcex3-aminobutyric Acid Analogues and 2,2-Disubstituted Pyrrolidinesxe2x80x9d 1991, J. Am. Chem. Soc. 113:9858 ).
Due to their biological activities and interesting structural features, it is also desirable to develop improved synthesis of lactacystin and clasto-lactacystin xcex2-lactone. New methodology for the construction of the lactam core in order to carry out targeted synthesis efficiently is also desirable.
For example, the biological activity of lactacystin and clasto-lactacystin xcex2-lactone (FIG. 1), is relevant to the regulation of apoptosis, an active research area for the development of anti-cancer treatments. The process of apoptosis (programmed cell death), which is regulated by the oncoprotein BcI-2, is targeted through the inhibition of the 20S proteasome, which overcomes the BcI-2 protective function and thereby induce cell death. Thus, specific inhibition of the 20S proteasome has been proposed for the selective destruction of cancerous cells but not normal cells. As a well-known specific inhibitor of the targeted proteasome, lactacystin has attracted considerable attention from synthetic chemists. Lactacystin is a natural product obtained from microbial metabolites, which induces neurite outgrowth in neuroblastoma cells as well as inhibits progression of human osteosarcoma cells. This natural product and its analog, clasto-lactacystin xcex2-lactone, also induce apoptosis in human monoblast cells. Because of scarcity and significant bioactivity, there is a need for economic total syntheses of these chiral pyrrolidinone compounds.
For synthesis of such chiral pyrrolidinones, amino acids are potential versatile starting materials. To effect the chiral pyrrolidinone synthesis, these amino acids require a ring closure reaction. In one approach, initramolecular Cxe2x80x94H insertion reactions of xcex1-diazoamide are used, catalyzed by rhodium salts. However, xcex1-diazoamides are poor substrates in ring closures through Cxe2x80x94H insertions, mainly due to competing side reactions, poor regioselectivities, and poor stereoselectivities (Table 1).
Common alternative methods employ the use of xcex1-diazoacetamides, xcex1-diazoacetoacetamides, and xcex1-diaomalonamides, which also give rise to regiochemical mixtures. Such reactions are performed at elevated temperature, and often provide low diastereoselectivities. Thus, each reaction gives poor yields and/or a complicated mixture of products, as illustrated below in Scheme A: 
It is a further object of the prevent invention to provide a means for synthesis bioactive compounds including, but not limited to, pramanicin, statine, AHPPA, kainic acid, rolipram, and eoplactaene.
The above and other features and advantages are achieved through the use of a novel synthetic method as herein disclosed. In accordance with one embodiment of the present invention, there is provided a method of synthesizing a lactam, the method comprising firstly providing an xcex1-diazoacetamide of structure (I), 
in which R1-6 are substituents that can include H, halo, N3, CN, NC, (C1-C22)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C2-C22)alkenyl, (C5-C8)cycloalkenyl, (C7-C32)aralkyl, (C7-C32)alkylaryl, (C9-C32)aralkenyl, (C9-C32)alkenylaryl, OR, SR, N(R)2, NH(R), CO2R, C(O)R, P(O)(OR)2, COR, CF3, S(O)R, or SO2R, wherein each R is independently H, (C1-C22)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C2-C22)alkenyl, (C5-C8)cycloalkenyl, (C7-C32)aralkyl, (C7-C32)alkylaryl, (C9-C32)aralkenyl, or (C9-C32)alkenylaryl; or R2 and R3 together comprise (C1-C22)alkyl, (C2-C22)alkenyl, (C7-C32)alkylaryl, (C9-C32)alkenylaryl, xe2x80x94C(CH3)2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(X)xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94C(X)xe2x80x94CH2xe2x80x94Oxe2x80x94, where n=0-10, and X is (C6-C10)aryl or (C7-C32)alkylaryl.
Secondly, the xcex1-diazoacetamide is reacted under conditions that promote intramolecular Cxe2x80x94H insertion, whereby a lactam is synthesized.
In accordance with another embodiment of the present invention, lactams synthesized by the foregoing method are provided. An exemplary lactam compound synthesized according to the method of the present invention is clasto-lactacystin xcex2-lactone.
In accordance with another embodiment of the present invention, a library of lactams synthesized by the foregoing method is provided, where such a library may be used, for example, in to screen for compounds having a desired biological activity.
Accordingly, a general synthetic method is desired that affords optionally substituted lactams in high yield, using economical conditions and reagents, comprising synthetic steps that cleanly provide product having the correct stereochemistry.
In addition, synthetic methods are also desired that economically provide libraries of chemically distinct lactams or compounds derived by further synthesis from lactams, for use, for example, in screening to identify biologically active lead compounds.
It is therefore a feature and advantage of the present invention, for example, to provide de novo methodology for the synthesis of the lactam core embedded in lactacystin and to refine this technology for general use. As depicted, for example, below, the Cxe2x80x94H insertion reaction of diazo compound 4 can lead to the formation of a xcex3-lactam, which is functionalized at every center. By varying substituents and structures, this method is expanded to formulate a large library of biologically significant lactams and compounds derived therefrom by further synthesis. 
It is another feature and advantage of the present invention to provide the synthetic plan described retrosynthetically in Scheme B. Lactacystin is prepared from bicyclic lactam 3 through sequential alkylation and aldol condensation, and pyrrolidinone 3 is synthesized by employing the aforementioned method. Several representative syntheses will be elaborated upon in this disclosure.
It is a further objective of the present invention to utilize expeditious synthesis of highly substituted xcex3-lactams and other lactams in an asymmetric manner. These cyclization products are for the total synthesis of numerous natural products and new compounds.
In accordance with yet another embodiment of the present invention, there is provided a compound synthesized from a lactam synthesized by the method of the present invention. Thus, a variety of natural and other compounds are provided that are synthesized using a lactam produced by the method of the present invention. Exemplary compounds, for which facile synthetic routes can be devised starting from suitable lactams produced according to the present invention, include, but are not limited to lactacystin, pramanicin, kainic acid, statine, AHPPA, rolipram, and salts and enantiomers thereof.
There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are, of course, additional features of the invention that will be described below and which will form the subject matter of the claims appended hereto.
In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of the method and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways, Also, it is to be understood that the phraseology and terminology employed herein, as well as the abstract included below, are for the purpose of description and should not be regarded as limiting.
As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.